piperidines and stearic-acid

Ibrutinib (IBR), an irreversible Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)-stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted immunotherapy. Amphiphilic egg phosphatidylglycerol (EPG) structure and strong IBR-EPG interactions render these nanocomplexes high IBR loading capacity, prolonged blood circulation, and optimal particle sizes (∼30 nm), which can effectively deliver IBR to the tumor, followed by subsequent internalization of IBR by TAMs through SA-mediated active targeting. In vitro and in vivo tests showed that the prepared SA/IBR/EPG nanocomplexes could preferentially accumulate in TAMs and exert potent antitumor activity. Immunofluorescence staining analysis further confirmed that SA/IBR/EPG remarkably inhibited angiogenesis and tumorigenic cytokines released by TAM and eventually suppressed tumor progression, without eliciting any unwanted effect. Thus, SA-decorated IBR nanocomplexes present a promising strategy for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Ibrutinib (IBR), an irreversible Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)-stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted delivery of IBR to TAMs. The developed SA/IBR/EPG nanocomplexes exhibited high efficiency in targeting TAMs and inhibiting BTK activation, consequently inhibiting Th2 tumorigenic cytokine release, reducing angiogenesis, and suppressing tumor growth. These results implied that the SA/IBR/EPG nanocomplex could be a promising strategy for TAM-targeting immunotherapy with minimal systemic side effects.

Topics: Adenine; Animals; Drug Delivery Systems; Immunotherapy; Macrophages; Male; Mice; N-Acetylneuraminic Acid; Nanoparticles; Neoplasms; Phosphatidylglycerols; Piperidines; Proton Magnetic Resonance Spectroscopy; Pyrazoles; Pyrimidines; Rats, Wistar; RAW 264.7 Cells; Stearic Acids

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), is an innovative non- radical scavenger used with success in numerous disease models such as inflammation, neurological disorders, hepatitis and diabetes. The pharmacological treatments have been performed by the intraperitoneal route of administration, representing to date, the main limit for the drug use. The aim of this study was to develop a delivery system that allows the oral administration of IAC while maintaining its therapeutic efficacy. Solid Lipid Microparticles (SLMs) containing a theoretical 18% (w/w) of IAC have been produced by the spray congealing technology; three formulations have been tested (A, B and C) using different low melting point carriers (stearic acid, Compritol(®) HD5ATO and carnauba wax) alone or in combination. All IAC loaded SLMs exhibited a spherical shape, encapsulation efficiency higher than 94% and particle size suitable for the oral route. Administered per os at different dosages in an inflammation rat model, all SLMs demonstrated their efficacy in reducing oedema and alleviating pain, compared to the gold standards Indomethacin and Paracetamol. These results suggested that the SLMs are an efficacious delivery system for the oral administration of IAC, potentially useful for the treatment of others diseases related to an over production of free radicals.

Topics: Acetaminophen; Administration, Oral; Animals; Disease Models, Animal; Free Radical Scavengers; Glycerol; Indomethacin; Inflammation; Liposomes; Male; Particle Size; Piperidines; Polyethylene Glycols; Rats; Stearic Acids; Waxes

To study the effect of different types of lipid on the entrapment efficiency (EE) and physical stability of repaglinide (RG)-loaded solid lipid nanoparticles (SLNs). RG-loaded SLNs were prepared by modified solvent injection method using stearic acid (RSA), glycerol monosteratae (RGM), glyceryl behenate (RGB) and tristearin (RTS). Poloxamer F68 was used as a stabilizer.. SLNs were characterized by particle size, zeta-potential, EE, in vitro release, solid-state properties (differential scanning calorimetry, transmission electron microscopy and electron diffraction) and stability at 30 degrees C/65% relative humidity for 3 months. The mean particle size and zeta-potential of RG-loaded SLNs prepared with different lipids in varying concentrations ranged from 150 to 355 nm and -21.04 +/- 3.10 to -30.54 +/- 2.76 mV, respectively.. EE was found to vary with lipids in the following order: RSA < RGM < RGB < RTS. Tristearin-prepared SLNs showed a significant prolonged drug release up to 24 h. Differential scanning calorimetry and electron diffraction microphotograph results indicated that RG entrapped in the SLNs existed in an amorphous or molecular state. SLNs prepared with stearic acid, glycerol monostearate and glyceryl behenate after storage showed significant increases in particle size, polydispersity index and EE. The SLNs prepared with tristearin were stable.

Topics: Administration, Oral; Calorimetry, Differential Scanning; Carbamates; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Stability; Excipients; Fatty Acids; Glycerides; Humidity; Hypoglycemic Agents; Kinetics; Lipids; Microscopy, Electron, Transmission; Nanoparticles; Nanotechnology; Piperidines; Poloxamer; Solubility; Stearic Acids; Technology, Pharmaceutical; Temperature; Triglycerides

Topics: Calcium; Calcium, Dietary; Chemical Phenomena; Chemistry, Physical; Cholinergic Antagonists; Hallucinogens; Parasympatholytics; Piperidines; Pressure; Research; Stearic Acids; Surface Tension; Viscosity